Immunoterapia Specifica

Azienda Ospedaliera di Verona Ospedale Civile Maggiore Unità Operativa di Allergologia

Specific Allergen Immunotherapy Leonard Noon

John Freeman

Prophylactic inoculation against hay fever

Vaccination against hay fever -results during the last 3 years-

Lancet 1911; 1: 1572

Lancet 1914; 1: 1178

Evoluzione dell’immunoterapia NOON

SLIT

ISHIZAKA

Uso empirico 1911

1986

IgE

RCTs

1966 SCIT

Allergoidi

SLIT 1986

2009

ROMAGNANI

CANONICA

Meccanismi-Studi Clinici Th1/Th2 Allergeni ricombinanti

Peptidi

1990

Liposomi, Adiuvanti

DURHAM

DNABased ITS

2009

INDICAZIONI ALL’IMMUNO TERAPIA NELL’ASMA

L’ITS è indicata nei pazienti con asma allergica, da lieve a moderata, specialmente quando l’asma è associata a rinite. Lo scopo è quello di ridurre i sintomi ed il consumo di farmaci, nonché di interferire con la storia naturale della malattia. L’immunoterapia ed il trattamento farmacologico non sono mutuamente esclusivi. L’immunoterapia non deve essere somministrata a pazienti con asma severa persistente o non adeguatamente controllata dalla terapia. Linee-Guida Italiane – Aggiornamento 2006

Allergic Rhinitis and its Impact on Asthma - ARIA

Attempt to interfere with the natural course of the disease should be introduced at a time where the patient has the capacity to respond positively. In this way immunotherapy does not take the position of being an ultimate treatment principle, but represents a supplement to drug treatment used in the early phase of the disease Aggiornamento Italia 2005

INDICAZIONI

lieve intermitt.

lieve Moderata- persistente grave intermitt.

Moderatagrave persistente

RINITE

IMMUNOTERAPIA

ASMA

Intermitte.

lieve moderata grave

CATEGORIE DI PROVA SPERIMENTALE Ia: risultati di meta-analisi di studi randomizzati controllati Ib: risultati da almeno uno studio randomizzato controllato IIa: risultati da almeno 1 studio controllato non randomizz. IIb: risultati di studi sper. non randomizzati né controllati III: studi comparativi, studi caso-controllo

IV: opinioni di panel di esperti o autorità scientifiche Shekelle PG et al. BMJ 1999; 318: 593-96

Subcutaneous Immunotherapy for Allergic Asthma Systematic Review and Meta-analysis • 75 DB PC RC studies were included (1954-2001) • Participants: n=3,506 (adults and children) • Patients with Allergic Asthma due to HDM (36), pollen (20), animal dander (10), moulds (2), latex (1), mixed (6) • Improvement in asthma symptoms • Reduction in Allergen PC20 • Reduction in non-specific bronchial hyperresponsiveness

Abramson M et al. In: The Cochrane Library, Issue 1, 2004

SCIT for Allergic Asthma Systematic Review and Meta-analysis SMD (95% CI)

p value

Symptom

-0.72 (-0.99,-0.44)

< 0.0001

Medication

-0.80 (-1.13,-0.48)

< 0.0001

Abramson M et al. In: The Cochrane Library, Issue 1, 2004

Subcutaneous Immunotherapy for Allergic Rhinitis Systematic Review and Meta-analysis • 51 DB PC RC studies were included (1950-2006) • Patients with Seasonal Allergic Rhinitis due to grass, tree or weed pollen • Participants: n=2,871 (1,645 active, 1,226 placebo) • Adults (children 1 study)

Calderon M et al 2007 Cochrane Reviews Jan 2007

Subcutaneous Immunotherapy for Allergic Rhinitis Systematic Review and Meta-analysis A wide range of allergens was administered in these studies: - mixed grass : - ragweed : - parietaria : - timothy : - birch : - orchard : - cedar : - bermuda : - juniperus ashei: - cocos :

16 studies 12 studies 6 studies 5 studies 4 studies 2 studies 3 studies 1 study 1 study 1 study

Calderon M et al 2007 in press Cochrane Reviews Jan 2007

Subcutaneous Immunotherapy for Allergic Rhinitis Calderon M et al 2007 Cochrane Reviews Jan 2007

SCIT for Seasonal Allergic Rhinitis Meta-analysis for nasal, bronchial and ocular symptoms and RQoLQ

Calderon M et al. Cochrane Collaboration 2007

JACI 2005; 116 : 961

Preventive effects of SCIT Long lasting effect Reduction of development of asthma Reduction of new sensitizations

Long-lasting effect of SCIT Long-term clinical efficacy of grass pollen immunotherapy Durham SR et al. N Engl J Med 1999; 341: 468-75 DB PC RCT, n=32, 3 years IT *Clinical improvement was accompanied by persistent alteration in immunologic reactivity

Twelve-year follow-up after discontinuation of pre-seasonal grass pollen immunotherapy in childhood Eng PA et al. Allergy 2006; 61: 198-201 Non-randomized controlled open study, n=22, 3 years IT * Reduction in onset of new sensitization was sustained 12 years later

Preventive effects of IT Long lasting effect Reduction of development of asthma Reduction of new sensitizations

“Effects of specific immunotherapy in allergic rhinitic individuals with bronchial hyperresponsiveness” Grembiale RD et al. Am J Respir Crit Care Med 2000 NO ASTHMA

Prevenzione dello sviluppo di asma dopo 3 anni

ASTHMA

60

40 32 19 SCIT

CONTROL

Moller et al. JACI 2002

Preventive effects of SCIT Long lasting effect Reduction of development of asthma Reduction of new sensitizations

SCIT Reduces New Sensitisations Children under 6 years with asthma (HDM sensitisation) 3-year follow-up 14 12

Number of Patients

12 10

10 8

8 6 6

6

6 4

4

2

2 0

6

SCIT Control

1

0 None

Cat

Dog

Alt

Grass

New Sensitivities Des Roches A et al. J Allergy Clin Immunol 1997; 99: 450-3

Prevention of new sensitizations in monosensitized subjects submitted to SIT or not. A retrospective study

Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific SIT. A six-year study

0.001

80 60 40

MONOSENSITIZED

% newly polysensitized 0.001

Drugs only SIT

80

60

40

20

20

After 4 years

After 7 years

Purello D’Ambrosio et al. Clin Exp Allergy 2001

Baseline

After 6 years

Pajno et al. Clin Exp Allergy 2001

“There is a good evidence from immunotherapy studies that a maintenance dose of 5-20 µ g of major allergen per injection is associated with significant improvement in patient symptom score.

J Allergy Clin Immunol 1998; 102: 558-62

160 140 120 100

Grains/m3

Randomised controlled trial with alum-adsorbed grass pollen extract for seasonal allergic rhinoconjunctivitis

Grains/m3

Pollen

80 60 40 20 0

9.00

1

2

3

4

5

7

8

9

10

11

100,000 SQ vs. Placebo P<0.001

7.00

Score Score

Symptoms

6 Wee k

8.00 6.00 5.00 4.00 3.00 2.00 1.00 -

UK Immunotherapy Study Group 26 centres, n=410 100,000 SQ, 10,000 SQ and placebo

Medication

Score Score

9.00 8.00

1

2

3

4

5

6

7

8

9

10

11

Week

7.00 6.00

100,000 SQ vs. Placebo P<0.001

5.00 4.00 3.00 2.00 1.00 1

Frew AJ et al, JACI 2006

Frew AJ et al, JACI, 2006

Reduction in symptom and medication score over placebo – whole season

2

3

4

5

6

7

8

9

10

11

Week Alutard 100,000 SQ

Alutard 10,000 SQ

Placebo

Rhinoconjunctivitis QoL score 3

Symptoms

p<0.001

2.5 2 1.5

Medication

p=0.027 P=0.027

1 0

10

20

30

40

50

Percent reduction Alutard 100,000 SQ median

Alutard 10,000 SQ median

60

p=0.027 P=0.027

0.5 0 Baseline

Frew AJ et al, JACI 2006

Season 100,000 SQ-U

Baseline/Season

10,000 SQ-U

Placebo

Frew AJ et al, JACI 2006

Systemic reactions (EAACI) Grade 0:

No symptoms

Grade 1:

Non-specific symptoms (i.e. discomfort, headache, fatigue, etc.)

Grade 2:

Mild systemic reactions (mild rhinitis or asthma responding adequately to antihistamines or salbutamol 100 µg inhalations)

Grade 3:

Non-life-threatening systemic reactions (generalised urticaria, angioedema or moderate/severe asthma)

Grade 4:

Anaphylactic shock (rapidly evoked reaction of itching, flushing, erythema, hypotension and severe bronchial obstruction etc, requiring intensive treatment).

Rands DA. Anaphylactic reaction to desensitization for allergic rhinitis and astma Br Med J 1980; 281: 854 Frankland AW. Anaphylactic reaction to desensitization Br Med J 1980; 281: 1429 Ewan PW. Anaphylactic reaction to desensitization Br Med J 1980; 281: 1069

Committee on the Safety of Medicines UPDATE: desensitive vaccine BMJ 1986; 293:948

• 26 fatalities 1957-1986 • 16/17 in patients with asthma

Author

Period

Fatalities

Lockey* 1959-84 24 (1987) Reid 1985-89 15 (1993) Bernstein* 1990-2001 17 (2004) *1 in a child of 5 years *4/17 between 10-18 years

Fatality rate/ injections 1 / 2.500.000 1 / 2.800.000 1 / 2.500.000

SCIT Adverse Events: Systemic Reactions Systematic Review and Meta-Analysis

Calderon M et al. Cochrane Collaboration 2007

Subcutaneous Immunotherapy for Allergic Rhinitis Use of Adrenaline

Calderon M et al. Cochrane Collaboration 2007

Evaluation of near-fatal reactions to allergen immunotherapy injections Amin et al. JACI 2006; 117 : 169  1 NFR / 1.000.000 injections Asthma present in 46% of NFR and 88% of fatal reactors Hypotension in 80% and respiratory failure in 10% of NFR and exclusively in asthmatics FR had prior emergency department visits and hospitalizations for asthma NFR experienced more often cutaneous symptoms Epinephrine was delayed for longer than 20 minutes or not administered in 30% FRs compared with 6% of NFRs

Safety of allergen-specific immunotherapy for inhalant allergy: a prospective study Senna G, Bonadonna P, Schiappoli M, Dama A Abstract EAACI Barcellona 2008  248 patients received 9.650 injections according to a traditional (204 p) and a cluster (44 p) schedule 19 SRs (0.20% of injections) were reported in 18 patients (7.3%) most (17) were mild (I-II°); Epinephrine was used only in 2 cases Grass gave most problems

Population study Tot. pts

males

females

248

140 108 (56.4%) (43.6%)

Age (mean yrs) 34.1 (7-67)

Allergen Total

Grass 87

Tree 31

Parietaria 76

Mite 51

Conventional

70

23

62

46

Cluster

17

8

14

5

Systemic Reactions

Total SRs

SR/Pt 18/248 (7,3%)

SR/Injection 18/9078 (0,20%)

Build up

13/248 (5,2%)

13/582 (2,23%)

Maintenance

5/248 (2,0%)

5/8496 (0,06%)

Le 5 SRs in fase di mantenimento sono tutte con GR

A PROSPECTIVE ITALIAN SURVEY ON THE SAFETY OF SUBCUTANEOUS IMMUNOTHERAPY FOR RESPIRATORY ALLERGY CEA 2009, submitted

1 Allergy Unit, General Hospital, Verona 2 Respiratory Diseases, University of Pavia 3 Allergic & Respiratory Diseases, Regional Hospital, Ancona

     11

12



4 Allergy Office, S.Carlo Clinic, Paderno Dugnano (MI) 5 Allergy Unit, C. Poma Hospital, Mantova 6 Allergy Office, Basic Health District, Tropea (VV)



7 Allergy Unit, Local Healthcare, Reggio Calabria 8 Allergy and Clinical Immunology, University of Bari 9 Department of Clinical Sciences, University of Parma 10 Allergy Unit, G.da Saliceto Hospital, Piacenza 11 Allergy & Respiratory Diseases, University of Genova 12 Allergy Unit, Occupational Medicin, University of Padova

 

A PROSPECTIVE ITALIAN SURVEY ON THE SAFETY OF SUBCUTANEOUS IMMUNOTHERAPY FOR RESPIRATORY ALLERGY 1.738 patients (847 male, age range 5-71) 2.038 courses SCIT (300 patients received two extracts) 60.785 injections with a mean immunotherapy duration of 3 years 95 reactions in 57/1.738 patients (3.28%) and 57/2.038 SCIT (4.7%) 1,56/1.000 injections. 25 patients experienced more than one adverse event 34 grade 2, 60 grade 3 and 1 grade 4 reactions and no fatality More frequently in asthma than in rhinitis alone (4,1% vs 1.1%, p= 0.03) Equally distributed between the build-up and the maintenance phase Ragweed and grass extracts caused significantly more side effects CEA 2009, submitted

Table 1. Demography and clinical characteristics of the subjects with or without SRs Pts with SR Pts without SR P (N= 57) (N= 1,681) NS for all decades 29.0 ± 15.6 33.3 ± 18.1 Age NS 24/33 823/858 Sex (m/f) OR= 0.76 (0.44-1.29) 42.1 48.9 % male Asthma (%) Rhinitis alone (%)

51 (89%) 6 (11%)

1,183 (70.3) 498 (29,7)

Table 2. Characteristics of the patients with SRs Asthma No asthma 51/1234 (4.1 %) 6/504 (1.1 %) Female Male 33/1,738 (1.9%) 24/1,738 (1.4%) Build-up - patients Maintenance - patients 28/57 (49.1%) 29/57 (50.9%) Build-up - reactions Maintenance – reactions 43/95 (45%) 52/95 (55%) Immediate onset - patients Late onset - patients 33/57 (57%) 34/57 (43%) Immediate onset - reactions Late onset – reactions 42/95 (44%) 53/95 (56%)

RR= 0.99 (0.97-1.1) 0.01 OR= 3.57 (1.5-8.4) RR= 1.04 (1.01-1.05)

p 0.03 NS NS NS NS NS Schiappoli M. et al. CEA 2009 in press

Table 3. Characteristics of the SRs Onset time <30’ >30’

Phase Mainte Buildnance up 23 25

N. Pts

N. SRs

Urticaria w/w angioedema

25

48

24

24

Rhinitis only Mild asthma° Asthma and Urticaria Severe asthma

12 10 7

16 18 10

9 6 6

7 12 4

11 11 6

5 7 4

2

2

2

0

1

1

Anaphylaxis

1

1

1

0

0

1

TOTAL

57

95

48

47

52

43

Symptom

° with/without rhinitis (grade 2)

Actions taken none or antihistamine with/without oral or i.v. steroid none or antihistamine inhaled albuterol albuterol+i.v.steroid+antihistamine (adrenaline in 1 patient) albuterol + i.m.adrenaline + i.v.steroid + oxygen albuterol +i.m adrenaline+ i.v steroid+ oxygen+ i.v.saline

the logistic regression analyses showed that ragweed extracts (OR= 5.032 [2.9-8.6]; RR= 1.08 [1.06-1.10]; p=.01) and grass extracts (OR=1.8 [1.04-3.1]; RR= 1.02 [1-1.04]; p=.04) were significantly associated with SRs

Antihistamine premedication in specific cluster immuotherapy: a DB PC study Nielsen L. JACI 1996

Reduction of side effects of specific immunotherapy by premedication with antihistamines Jarisch R. 1988

Reduction of side effects from rush-immunotherapy with honey bee venom by treatment with terfenadine Berchtold E. Clin Exp Allergy 1992

Omalizumab pretreatment decrease acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis Casale TB. JACI 2006

stetoscopio e sfigmomanometro ✸ lacci, siringhe ed aghi di diverse misure ✸ ADRENALINA ✸ ossigeno ✸ set per infusione di liquidi ✸ cannule orofaringee ✸ pallone Ambu ✸ antistaminici, steroidi ✸

Specific immunotherapy among Italian specialists C. Lombardi, GE Senna, G Passalacqua

Allergy 2006: 61:898-899 - july

Desensitizing vaccines 26 deaths due to SCIT Committee on the Safety of Medicines BMJ 1986; 293:948

Non-injection routes for immunotherapy ... the overall aim of improving safety of immunotherapy and making it more convenient for the patients... EAACI IT Position Paper 1993

SLIT IN THE OFFICIAL DOCUMENTS A promising route…. More data are needed… Risk of too rapid absorption...

EAACI Pos Pap 1993

NOT CONSIDERED BSACI Pos Pap 1993

…a viable alternative to SCIT in adults… ..safety in children has to be confirmed…. WHO Pos Pap 1998

SLIT can be administered in adults and children... ARIA Pos Pap 2001

SLIT vs SLIT “More than 50% of the current population of patients in Central Europe receiving specific immunotherapy are on SLIT” Bousquet J & Demoly P. Allergy 2006; 61: 1155 -1158 FRANCE 90 80 70 60

%

50

SLIT

40

SCIT

30 20 10 0 2002

2003

2004

2005

2006

Year

ITALY 80 70 60 50

% 40

SLIT

30

SCIT

20 10 0 2002

2003

2004 Year

Staloral (Stallergènes); SLIT 1, Grazax (ALK-Abello); TOL (Leti); ALLERSLIT Forte (Allergopharma)

2005

2006

( july )

… I also hope that pro and con sessions will cease on SLIT as it has now been validated !

Sublingual Immunotherapy for Allergic Rhinitis Systematic Review and Meta-analysis • 22 DB PC RC studies were included (1986-2002) • Patients with Seasonal and Perennial Allergic Rhinitis • Participants: n=959 (484 active, 475 placebo) • Adults (16 studies), children (5 studies), mixed (1 study) Wilson D et al. Allergy 2005; 60: 4-12

SLIT for Allergic Rhinitis Meta-analysis: Symptom scores

• Subgroup analysis: seasonal allergens better than perennials • Better > 12 months’ duration

Wilson D et al. Allergy 2005; 60: 4-12

SLIT for Allergic Rhinitis Meta-analysis: Medication scores

• Subgroup analysis: seasonal allergens better than perennials • Better > 12 months’ duration

Wilson D et al. Allergy 2005; 60: 4-12

Sublingual Immunotherapy for Allergic Rhinitis Systematic Review and Meta-analysis • SLIT is effective compared to placebo • SLIT is safe with only minor local side effects • Comparative studies, long-term studies and more pediatric studies are needed

Sublingual Immunotherapy in Allergic Asthma Systematic Review and Meta-analysis •

25 DB PC RC studies were included (1966-2005)

•

Patients with Allergic Mild-Moderate Asthma

•

Allergens administered: mites (10), pollen (14), mixture (2) and latex (1)

•

Participants: n=1,706

•

Adults and children (10 studies)

•

Duration: 3 months to 3 years

•

Extracts given as drops and then swallowed, with the patient fasting Calamita Z et al. Allergy 2006; 61: 1162-72

SLIT for Allergic Asthma Meta-analysis: Symptom score Calamita Z et al. Allergy 2006; 61: 1162-72

Allergy, october 2006 ; pp. 1162-72

Sublingual Immunotherapy for Allergic Rhinitis in Children Systematic Review and Meta-analysis •

10 DB PC RC studies were included (1990-2004)

•

All patients had allergic rhinitis: 59% asthma and 73% conjunctivits

•

Participants: n=484 (245 active, 239 placebo)

•

Age range: 3 to 18 years

Penagos M et al. Ann Allergy Asthma Immunol 2006; 97: 141-48

META-ANALYSIS OF THE EFFICACY OF SLIT IN RHINITIS IN PEDIATRIC PATIENTS

10 studies

Penagos M, Compalati E, Baena-Cagnani R, Passalacqua G, Canonica GW Ann Allergy Asthma Immunol 2006

SYMPTOMS

MEDICATIONS

Sublingual Immunotherapy for Allergic Rhinitis in Children Systematic Review and Meta-analysis SMD (95% CI)

p value

Symptom

-0.56 (-1.01,-0.10)

= 0.02

Medication

-0.76 (-1.46,-0.06)

= 0.03

• Subgroup analysis: pollen better than mites • Better > 18 months’ duration Penagos M et al. Ann Allergy Asthma Immunol 2006; 97: 141-48

Efficacy of sublingual allergen vaccination for respiratory allergy in children. Conclusion from a meta-analysis Olaguibel & Alvarez Puebla J Invest Allergol Clin Immunol 2005; 15 : 9

 7 dbpc trials enrolling 256 children (129 treatemnts; 127 placebo) were analyzed; decrease in symptoms (SMD : -1.42 for asthma; - 0.44 for rhinitis and – 1.49 for conjunctivitis) and medications requirement (SMD : - 1.09) ; Only reductions in asthma (p= 0.01) and drug dosage (p= 0.06) scores reached statistical significance; Safety was constant in all the studies

Preventive effects of SLIT Long lasting effect Reduction of development of asthma Reduction of new sensitizations

Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a ten-year prospective study V.Di Rienzo, F.Marcucci, P.Puccinelli, S.Parmiani, F.Frati, L.Sensi, GW Canonica, G. Passalacqua Clin Exp Allergy, 2003

35 SLIT + drugs

60 pts

25 only drugs 0

5

YEARS

10

Long-lasting effect of SLIT Children with asthma due to HDM 10-year open prospective study p<0.01

450 400

• SLIT 4-5 years • Control: only treatment

350 300 PEFR (L/mim) Mean

250 200

SLIT (n=22)

150

Controls (n=16)

100 50 0 Baseline

End SLIT

10 years

Di Rienzo V et al. Clin Exp Allergy 2003; 33: 206-10

Preventive effects of SLIT Long lasting effect Reduction of development of asthma Reduction of new sensitizations

SLIT Reduces Risk of Developing Asthma Children (5-14 yo) with Allergic Rhinoconjunctivitis 3-year follow-up (n=113) Odds ratio 3.80 (1.5-10.0)

% of patients

100%

• Open, randomized study • SLIT for 3 years • Symptomatic treatment

n=37

80%

n=26

60%

80%

40% 20%

n=18 60%

w asthma w/o asthma

n=8 20%

40%

0%

SLIT

Control

Novembre E et al. J Allergy Clin Immunol 2004; 114: 851-7

Preventive effects of SLIT Long lasting effect Reduction of development of asthma Reduction of new sensitizations

SLIT Reduces New Sensitisations Randomized controlled open study of SLIT for respiratory allergy in real-life: clinical efficacy and more Marogna M et al. Allergy 2004: 59: 1205-10

n=511 with AR +/- intermittent asthma Two groups: SLIT+drugs or drugs only for 3 years New sensitizations appeared in 38% of the controls and 5.9% of the SLIT patient (p=0.01)

SLIT - SIDE EFFECTS Local:

oral itching-swelling stomach-ache nausea-vomiting

Systemic: Urticaria/angioedema Rhinitis Asthma Anaphylaxis

SLIT Adverse Events: Systemic Reactions Systematic Review and Meta-Analysis

All of the studies included reported a complete absence of systemic effects * Minor local side effects consisting of itching and swelling of the oral mucosa were reported almost universally but were rarely of significance. Wilson D et al. Allergy 2005; 60: 4-12 * Penagos M et al. Ann Allergy Asthma Immunol 2006; 97: 141-48

* GI, nasal-ocular, asthma, urticaria

SLIT: POST MARKETING SURVEYS Author

N pats Age range

Followup

AE % of patients

AE/1,000 doses

Di Rienzo

268

2-15 years

3 years

3%

0.1/1,000

Lombardi

198

> 14 years

3 years

7.5 %

0.5/1,000

Pajno

354

5-15 years

36 months

6%

0.15/1,000

Agostinis

36

3-5 years

2 years

5%

0.07/1,000

Di Rienzo

128

3-5 years

2 years

5. 6%

0.2/1,000

80% local mild transient

Characteristics of reported systemic side-effects 198 pts, 1 to 3 years of SLIT % OF SIDE EFFECT

EPISODES

GRADE

PATIENTS

TIME OF ONSET

Conjunctivitis

1

0.5

Moderate

45 min

G.I. complaints

3

1.5

Mild

30-120 min

Rhinitis

7

3.5

Mild

< 60 min

Urticaria

3

1.5

2 mild

> 30, <60 min

1 moderate Oral itching

3

1.5

Mild

< 30 min

Angioedema

0

-

-

-

Asthma

0

-

-

-

Anaphylaxis

0

-

-

-

TOTAL

17

8.6

15 mild

-

2 moderate

Lombardi C et al. Allergy 2001

Safety of SLIT in children and adults No difference between active and placebo in rhinitis, conjunctivitis, asthma, laryngeal edema and urticaria occurence. Gastrointestinal effects: in adults 67 active and 12 placebo in children 41 active and 60 placebo No difference between children and adults for adverse events occurrence.

Andrè C. et al. Int Arch Allergy Immunol 2000

The age below 5 years is a relative contraindication for injection Immunotherapy, mainly for safety reasons…. WHO Position Paper, 1998

WHAT ABOUT SLIT?

Post-marketing survey on the safety of sublingual immunotherapy in children below the age of 5 age Di Rienzo et al. Clin Exp Allergy 2005; 35: 560

Safety of SLIT in children below the age of 5: Post-marketing survey SLIT

N (%)

SEX M/F

MEAN AGE (range)

Mono sensitized

DISEASE*

House dust mite (3 + Alternaria)

78 (62)

36/42

4,16 (3-5)

54

13 R, 14 A 51 R+A

Grass (4 + olive / 1 + Alternaria)

28 (22)

17/11

4,14 (3-5)

16

10 R, 18 R+A

Olive

2 (2)

1/1

4,5 (4-5)

1

1R 1 R+A

Parietaria

15 (12)

11/4

4,6 (3-5)

6

9 R, 2 A 4 R+A

Alternaria

3 (2)

2/1

4,3 (4-5)

2

1R 2 R+A

Total

126

67/59

4,2 (3-5)

79

34 R, 16 A 76 R+A

Di Rienzo V, Musarra A, Minelli M, Sambugaro R, Pecora S, Canonica GW, Passalacqua G. Clin Exp Allergy 2005

Pt

Sex

Age Side effect

Allergen

Grade

Onset time

Action taken

1

M

3

Oral itching

Mite

Mild

15 min

None

2

M

4

Oral itching

Mite

Mild

10 min

None

% 1 . 7 : S s T C e s E o F d F 0 E 0 E 0 . D I 1 / S 2 . 9 0 d n a

e i t a

s t n

p

3

F

4

Abdominal pain

Mite

moderate

30 min

None

4

F

5

Abdominal pain-diarrhea

Mite

moderate

2 hrs

Spit

5

F

5

Diarrhea

Mite

moderate

1 hrs

Spit

6

M

4

Diarrhea

Mite

moderate

1 hrs

Spit

7

M

5

Diarrhea

Grass

moderate

2 hrs

Spit

8

M

4

Abdominal pain-diarrhea

Grass

moderate

30 min

Spit

9

F

5

Diarrhea

Parietaria moderate

2 hrs

Spit

Agostinis F, Tellarini L, Canonica GW Passalacqua G Allergy 2005; 60 : 133

Safety of sublingual immunotherapy with a monomeric allergoid in very young children  36 children (mean age 3 yrs 2 months) were enrolled; mean follow-up was 22.2 months and the number of doses was 25.200; One episode of abdominal pain occured in two children (5% of patients – 0.071 per 1.000 doses)

SLIT No fatal or near-fatal event reported since 1986

Physical exercise does not favour adverse reactions to allergen immunotherapy by sublingual route Senna G, Bonadonna , Crivellaro MA et al, Eur Ann Allergy Clin Immunol 2005; 37 : 58

Parameter Before clinical exercise FEV 1 97.09 +/- 10.05

After physical exercise

BP (mmHg) 121.91 +/- 125 +/- 13.3

125.45 +/- 8.2

Heart rate 82.6 +/- 9.2

87.0 +/- 12.7

Tryptase

5.81 +/- 4.43

5.57 +/- 4.54

95.73 +/- 11.29

SCIT - SLIT Comparison of clinical efficacy The double-blind, double-dummy design is the gold standard

+2

0.002

+1.4

MEAN CHANGE DAILY SYMPTOM SCORE

+1 +2 0 -1 -2

0.002

+0.3 -0.4

+1

+0.2 NS

NS

0

MEAN CHANGE DAILY MEDICATION SCORE SCIT

-1

SLIT PLB

Khinki et al. Allergy 2004

-2

-0.3 -0.6

Cochrane meta-analyses of immunotherapy for allergic rhinitis

SCIT SMD (95% CI)

Symptoms

- 0.71 (-1.11,-0.30) z=3.4, p=0.0006

Medication

SLIT SMD (95% CI)

- 0.42 (-0.69,-0.15) z=3.1, p< 0.002

- 0.84 (-1.31,-0.37)

- 0.43 (-0.63,-0.23)

z=3.5, p=0.0005

z=4.2, p<0.0003

Calderon M et al, 2005

Wilson D et al, 2005

SYSTEMIC IMMEDIATE SIDE EFFECTS SCIT

SLIT

PLA

Grade II

23

33

36

Grade III

5

0

1

Grade IV

1

0

0

SLIT showed significantly fewer and milder side effect compared with SCIT Khinki et al. Allergy 04

EFFECTS

Risk/benefit in IT SCIT

SIDE

SLIT OIT 0

25%

>50%

CLINICAL EFFICACY Malling, 2006

Experimental Evidence for Immunotherapy SCIT

SLIT

Ia Ia Ib Ib IIb IIb Ia

Ia Ia Ia IIa IIb IIb Ia

Clinical efficacy: Rhinitis Clinical efficacy: Asthma Clinical efficacy: Children (AR) Long-term effect Prevention of new sensitizations Prevention of asthma Safety Ia Ib IIa IIb

Evidence from meta analysis of RCT Evidence from at least one RCT Evidence from at least one controlled trial without randomization Evidence from at least one other type of quasi experimental trial

Specific Allergen Immunotherapy: Risk & Benefit Efficacy ++ Safety +

Efficacy + Safety ++ SLIT

SCIT

Specific Allergen Immunotherapy: Risk & Benefit Efficacy ++ Safety +

Efficacy + Safety ++ SLIT

SCIT

Patient selection !

Experimental Evidence for Immunotherapy Conclusions •

More PC, DB and RC studies are needed with standardization of symptom scores

•

Characterization of participants (disease severity)

•

Lack of studies in children

•

Number of patients recruited (sample size and power calculation)

•

Safety in high-risk groups

Experimental Evidence for Immunotherapy Conclusions • Quality of vaccines: standardization • Duration treatment: pre-season and maintenance • Schedule: up-dosing and maintenance • Dose: units of major allergen protein • Adverse events • Cost

Azienda Ospedaliera di Verona Ospedale Civile Maggiore Unità Operativa di Allergologia G. Senna P. Bonadonna M. Conte A. Dama E. Olivieri M. Schiappoli

Centro regionale di riferimento per la prevenzione, la diagnosi e la terapia delle malattie allergiche

Collaborations A. Romano (Roma) B. Caruso (Verona) P. Gisondi (Verona) C. Le Pera (Verona) R. Zanotti (Verona) S. Durham (Londra) M. Pagani (Mantova) M. Calderon (Londra) L. Castellani (Trento) C. Lombardi (Brescia) M. Crivellaro (Padova) L. Antonicelli (Ancona) G.W. Canonica (Genova) G. Passalacqua (Genova)